Malaria is one of the world's most devastating diseases. Drug resistance is rapidly rendering our antimalarial armamentarium obsolete. The goal of the proposed research project is to understand at a molecular level and ultimately to inhibit the function of the aspartic proteases of the human malaria parasite, Plasmodium falciparum. The parasite grows by catabolizing host erythrocyte hemoglobin and using the resulting amino acids for protein synthesis. The PI has shown that aspartic protease action unravels the hemoglobin molecule by strategic cleavage, exposing for further, efficient proteolysis. Aspartic protease inhibitors that block hemoglobin degradation kill P. falciparum parasites in culture. A family of aspartic protease genes exists in the falciparum genomic database. The PI proposes to examine the expression, location, biosynthesis, enzymology, substrate specificity and function of the encoded aspartic proteases. The goal is to better understand the roles of aspartic proteases in parasite biology generally and in hemoglobin degradation specifically, with an eye toward future drug development.